Intensive glucose treatment (maintaining plasma glucose at normal levels) in type 1 DM patients can delay the onset and slow the progression of microvascular complications. Unfortunately, intensive therapy is associated with an ~ threefold increase in severe hypoglycemia. Exercise, which improves glycemic control, insulin sensitivity, and quality of life, is an important clinical adjunct to diabetes treatment. Unfortunately, exercise also increases the incidence of hypoglycemia, but the mechanisms for this are not clearly understood. Thus, the aims of this proposal are to determine in type 1 DM: 1) whether the metabolic consequences following antecedent hypoglycemia or prior exercise will significantly alter the ability of an individual to defend against same day hypoglycemia and 2) whether following antecedent hypoglycemia, exercise in the presence of modest hyperinsulinemia will lead to substantial deficits in metabolic counterregulatory mechanisms. We will use glucose clamping and exercise and to assess neuroendocrine (plasma glucagon, catecholamines, growth hormone, cortisol, ACTH, and pancreatic polypeptide), in vivo metabolism (glucose and glycerol turnover, substrate levels, and substrate oxidation via indirect calorimetry), and muscle sympathetic nerve activity to thoroughly study these specific aims. The studies will allow us to elucidate in-vivo mechanisms responsible for counterregulatory failure during exercise related hypoglycemia in type 1 DM and to identify new treatment strategies to prevent this problem.